The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and
uniquely requires primary cilia. Functional analyses of several
ciliogenesis-related genes led to the discovery of the developmental
diseases known as ciliopathies. Hence, identification of mammalian factors
that regulate ciliogenesis can provide insight into the molecular
mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that
DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss
of Dyrk2 in mice causes suppression of Hh signaling and results in
skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2
induces abnormal ciliary morphology and trafficking of Hh pathway
components. Mechanistically, transcriptome analyses demonstrate
down-regulation of AurkA and other disassembly genes following Dyrk2
deletion. Taken together, the present study demonstrates for the first
time that DYRK2 controls ciliogenesis and is necessary for Hh signaling
during mammalian development.

哺乳动物Hedgehog（Hh）信号通路在胚胎发生过程中发挥关键作用，且特异性依赖初级纤毛（primary cilia）。多项针对纤毛发生相关基因的功能分析，推动了一类被称为纤毛病（ciliopathies）的发育疾病的发现。因此，鉴定调控纤毛发生的哺乳动物因子，可为胚胎发生与纤毛病的分子机制研究提供新的见解。本研究证实，DYRK2是一种新型的哺乳动物纤毛发生相关蛋白激酶。小鼠体内Dyrk2基因缺失会抑制Hh信号通路，并在体内胚胎发育过程中引发骨骼异常。Dyrk2基因的缺失会导致纤毛形态异常，同时影响Hh通路组分的转运。从机制层面分析，转录组分析显示，Dyrk2缺失后，AurkA及其他纤毛解聚相关基因的表达出现下调。综上，本研究首次证实，DYRK2可调控纤毛发生，且在哺乳动物发育过程中对Hh信号通路的正常行使至关重要。